The Bode group, now at ETH-Zurich, discloses in JACS ASAPssome intriguing bifunctional acylboronates. Much like their MIDA boronate cousins, these, too, are stabilized by an N,O-chelating ligand, demonstrate a shelf-life of several months, and are easily prepared in one step from their potassium trifluoroborate salts.

Do you suppose these reagents could survive the strongly basic aqueous conditions used for MIDA deprotection and subsequent cross-coupling? The authors, comparing MIDA-acylboronates against NOF-acylboronates under aqueous hydrolysis conditions, claim:

"In all cases, the bidentate, monofluoroacylboronates were much more stable than the MIDA variants and should be sufficiently stable* for most applications."

If this holds true, one could imagine capping Burke's automated syntheses with carboxylic acid derivatives without resorting to bulky t-Bu esters or exotic silyl-protected esters.

*Now I'm just brainstorming, but could catalytic conditions be found to transmetalate the acylboronate to, say, Rh or Pt?

I've stared at that picture a looong time. Funny - the Lego blocks seem intended to symbolize how Burke's new system renders synthesis highly modular...perhaps that it's even child's play.

The asterisk in each line drawing (at right) represents where the artist holds the secodaphnane core. The entire structure, as pictured, is "flipped" such that it the two syn methyl groups (red and green in Burke's representation) should be touching the table. That conformation gives me twitches; nothing's quite where it should be in 3D space! I almost wonder if it's not hooked up quite right...

Sometimes, molecules make for capricious photo subjects. But I can't grok the way that one looks. Anyone else agree?

Trudging along through chemical space, using Dr. Reymond's MQN-browser.
(I realize there's no way some of these are stable - 49? 54? - but they sure do look cool!)

Of these innumerable options, how do we decide what to make next? It's like that old Wall Street saw about how "Buy low, sell high" sounds easy, but takes a lifetime to figure out. It seems straightforward to say that you've generated billions of druglike compounds in silico, but how do you find out which ones are actually drugs?

You have to start somewhere. I still recall the first "chemical space exploration" paper that truly caught my eye - a 2009 J. Med. Chem. scribed by Will Pitt and colleagues at UCB (I still keep a dog-eared copy in my file cabinet). Using machine learning, the team constructed a library (VEHICLe) containing synthetically feasible heterocyclic compounds, most of which had never been made.

Offering a partial update to Will Pitt's "Figure 6" from his 2009 J. Med. Chem.I searched SciFinder for each ring system as a substructure of reaction products, allowing for certain substitutions (say, fused phenyl in place of endocyclic olefin) and considering tautomers. By my count: 10 down, 12 to go!

Pitt issued a challenge in the introduction:

"With this work, we aim to provide fresh stimulus to creative organic chemists by highlighting a small set of apparently simple ring systems that are predicted to be tractable but are, to the best of our knowledge, unconquered."

Heady stuff. So, who will step forward to try these tantalizing targets? Someone certainly should, as Prof. Reymond seems to suggest with his own forward-leaning graphic:

Do you suppose an academic candidate could make a convincing case? I'd be tickled pink if something along these lines were sent off to the NIH R01 office:

"Dear [insert funding agency] - Listen, I really want to develop novel molecules to improve human health, but I'm not collecting plants or culturing microbes, and it's too tough to compete with industry head-on. But say, there's this guy who's looked at more compounds than any other human being alive, and he says there's some structures that look really close to existing drugs that nobody's ever tried making. Mind giving me some cash for that?"

My Freshman year at Big State University passed unceremoniously, as many do. Made lots of cultural and personal adjustments. Some courses aced, some classes ignored, all in pursuit of a major I thought I enjoyed. Enter Sophomore year, when I had the standard eye-opening, life-altering epiphany all self-identified organikers have upon taking O-Chem 201. But that's not where My Big Break(TM) occurred.

Fast forward to the weekly Chem Colloquium, in which speakers from the outside world came in to advise we burgeoning chemists how life looked on the other side of college. Once, a wild-haired, soft-spoken gentleman visited from the Big City. He worked in pharmaceutical chemistry, and I'll never forget something he said at the end of his talk: "Interns Wanted." Yes, we were being pitched to finish his presentation! At that moment, years of summer toil checking bags, cleaning parking lots, mopping floors, updating registers,* sharpening pencils*, and preparing transparencies* paled in comparison to WORKING IN BIOTECH. I somehow bulled my way to the front of the lecture hall in time to grab the last open slot on his roster.

The rest, as they say, is history...

--
*This was before the Internet, tablet PCs, and wide adoption of PowerPoint. Ask your parents.

Monday, March 2, 2015

Accounts of Chemical Research - located at the "left of your ACS radio dial"- may be as unloved as the random college radio stations one finds there. Yet it somehow seems to be catching fire with the chemistry "It" crowd.

Seriously...it's on the left!

I'd heard plenty of knocks back in grad school: "Self-reviews." "Citation fluffing." But, know what? I can't help but want to read most of these recent papers.

See Arr Oh

Who is this masked chemist?

Finding my way through new challenges.
I was a founding blogger at Scientific American's Food Matters and Blog Syn. I once wrote for C&EN's The Haystack. I've written for Nature Chemistry, Newscripts, Chemistry Blog, Chemjobber, and Totally Synthetic.